A Randomized Clinical Trial Investigating the Relationship Between Aprotinin and Hypercoagulabilityin Off-Pump Coronary Surgery

Thrombin is the central enzymatic mediator of both hemostasis and thrombosis. Thrombin produced in a controlled fashion creates fibrin polymers critical for hemostasis while a larger burst activates platelets via its high affinity thrombin receptor, protease-activated receptor-1 (PAR-1), leading to a platelet-rich clot and thrombosis.1 Blood collected from standardized bleeding time skin incision on the forearm provides a model of hemostasis in response to microvascular injury.2,3 Because surgically grafted vessels always develop some degree of perioperative endothelial disruption,4 they provide a “model” of macrovascular injury. Blood sampled from the coronary sinus (CS) downstream of these grafts provides a unique opportunity to assay the regional thrombotic response to this injury.5 We have documented a significant increase in regional thrombin production downstream of saphenous vein grafts (SVGs) after off-pump as compared with on-pump coronary artery bypass graft (CABG),6 with the level of thrombin produced directly related to the risk of early SVG failure.5 This heightened regional thrombin production is particularly noteworthy in light of recent meta-analyses demonstrating that the risk of early SVG failure is increased after off-pump coronary artery bypass (OPCAB) grafting.7,8 PAR-1 receptor antagonists have demonstrated the ability to target the cellular actions of thrombin on platelets while leaving the hemostatic actions of thrombin in the coagulation cascade untouched.9 The hemostatic agent, aprotinin, has been shown to be an antagonist of PAR-1 at pharmacologically relevant doses.10,11 This inhibitory effect would be predicted to provide clinical antithrombotic actions on platelets within the macrovasculature without hindering hemostatic plug formation in the microvasculature at wound sites where alternate platelet agonists (e.g., collagen and adenosine diphosphate [ADP]) are generated.12 On the other hand, aprotinin also inhibits fibrinolysis, which raises the concern that it might increase the risk of thrombosis. Although the link between aprotinin and thrombosis has endured “twenty-five years of claim and counterclaim,”13 there have been essentially no clinical studies on the mechanism of how aprotinin may cause thrombosis. The purpose of the study was to test the hypothesis that aprotinin administration would inhibit the pathologic burst in thrombin production produced within grafted macrovessels but not physiologic thrombin required for wound hemostasis.